The primary goals of this project are to develop and validate electronic phenotyping algorithms, to accurately identify cases and controls, and to conduct a genome wide association study that advances understanding of two specific yet interrelated disease states, while simultaneously engaging the community in these research efforts. A secondary goal is to build upon the existing infrastructure necessary to further subsequent genome wide studies, positioning the PMRP biobank as a national resource. Lipid abnormalities and cataracts are both diseases of public health significance, they share common risk factors (and prevention or management with statins), and they are both complex diseases which likely have many genes contributing to disease development. Whole genome association studies with these two outcomes and environmental risk factors could yield novel data about the etiology of the two separate outcomes as well as their interaction. The specific aims of the study are as follows: 1a) to develop and validate two primary outcomes, low HDL and cataract, in the Marshfield Clinic PMRP, and to quantify the impact of two environmental factors (cigarette smoking and statin use) known to influence each of the primary study outcomes, 1b) to evaluate the validity of electronic algorithms developed in the context of different electronic medical records in the Marshfield Clinic EMR, 1c) in conjunction with the other funded sites, to develop standards for electronic phenotyping, 2) to conduct community consultation activities, define issues essential to the appropriate conduct of whole genome association studies, and maximize data sharing without compromising data security or confidentiality, 3a) elucidate combinations of genetic markers that predispose subjects to the development of cataract, 3b) further our understanding of the genetic architecture underlying low circulating levels of HDL cholesterol, and 3c) quantify the degree to which low HDL levels contribute to the onset and progression of cataracts in this population-based cohort, and to parse the genetic risk factors identified through whole genome scanning as being contributory to either low HDL cataract, or both, and explore gene/environment interaction with cigarette smoking and statin use. These aims will be studied in a nested case control study of 4220 cases (3037 low HDL, 1609 cataract surgery, 426 with both conditions) and 1481 controls aged 55 and older who have neither condition and have been screened for both conditions in the past five years. Quarterly meetings of the PMRP Community Advisory Group and quarterly newsletters will be used to engage and inform the public about this whole genome association study and the sharing of data with the wider research community. Multi-factor dimensionality reduction analyses will be used to prioritize SNPs for replication in other cohorts. The strength of the research team and the depth and breadth of the electronic medical record at the Marshfield Clinic make this the ideal setting for this RFA. [unreadable] [unreadable] [unreadable]